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This invention relates generally to preparing nonracemic chiral alcohols. It is directed to a novel process for the preparation of a nonracemic diastereomer of 1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol compounds of the formula I or a stereoisomer thereof, wherein R is hydrogen or a hydroxyl-protecting group. 
This invention more specifically relates to preparing nonracemic chiral alcohols by asymmetric hydrogenation of ketones. It is directed to the preparation of compounds of the formula I by asymmetric hydrogenation of the corresponding nonracemic ketone compound of formula II or its enantiomer. 
Compounds of formula I are useful as pharmaceutically active compounds and as intermediates thereto. For example, the nonracemic compound of formula I having the (1S,2S) stereochemical configuration, wherein R is hydrogen, exhibits potent NMDS (N-methyl-D-aspartic acid) receptor antagonist activity and is useful in the treatment of traumatic brain injury and other central nervous system conditions. Corresponding compounds wherein R is an alkyl group or a hydroxyl-protecting group are useful in the preparation of the compound of formula I wherein R is hydrogen.
Ketones can be converted to racemic chiral alcohols by hydrogenation using certain catalyst systems of ruthenium, a phosphine ligand, a 1,2-diamine, and an alkaline base. Aromatic and heteroaromatic ketones can be hydrogenated to nonracemic chiral alcohols by using certain catalyst systems of ruthenium, an appropriate enantiomeric diphosphine ligand, an enantiomeric 1,2-diamine, and an alkaline base. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; U.S. Pat. No. 5,763,688; J. Am. Chem. Soc., vol. 117 (1995), 2675-2676; J. Org. Chem., vol. 64 (1999), 2127-2129. Similarly, such ketones can be hydrogenated to nonracemic chiral alcohols by using corresponding catalyst systems formed using a racemic chiral 1,2-diamine, wherein the active diastereomeric ruthenium catalyst is formed with the enantiomeric diphosphine ligand and the xe2x80x9cmatchedxe2x80x9d enantiomer of the racemic chiral 1,2-diamine, and the diastereomeric ruthenium complex with the xe2x80x9cunmatchedxe2x80x9d enantiomer of the racemic chiral 1,2-diamine, if it is formed, is relatively inactive. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; European Patent Application 0,901,977; J. Am. Chem. Soc., vol. 120 (1998), 1086-1087. A catalyst system of ruthenium, S-2,2xe2x80x2-bis(diphenyl-phosphino)-1,1xe2x80x2-binaphthyl (S-BINAP), achiral ethylene diamine, and potassium hydroxide in isopropanol is reported to hydrogenate 1xe2x80x2-acetonaphthone to (R)-1-(1-naphthyl)ethanol in 57% enantiomeric excess. The corresponding catalyst system having enantiomeric (S,S)-1,2-diphenyl-ethylenediamine instead of achiral ethylene diamine is reported to hydrogenate 1xe2x80x2-acetonaphthone under the same conditions to (R)-1-(1-naphthyl)ethanol in 97% enantiomeric excess. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; J. Am. Chem. Soc., vol. 117 (1995), 2675-2676.
An earlier method (U.S. Pat. No. 5,716,961) for the preparation of enantiomeric (1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol (formula I, R=H) involves the steps of: 1) a hydride reduction of the racemic ketone corresponding to formula II having R=benzyl to produce the racemic syn-enantiomers (equal parts (1S,2S) and (1R,2R) configurations) of formula I having R=benzyl; 2) debenzylation by catalytic hydrogenolysis to produce the racemic syn-enantiomers of the formula I having R=H; 3) diastereomeric salt resolution of the racemic syn-enantiomers using D-(xe2x88x92)-tartaric acid to produce the D-tartrate salt of the (1S,2S)-enantiomer of formula I having R=H; and 4) neutralization of the D-tartrate salt to produce the free base (1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol (formula I, R=H). The free base is further reacted with methanesulfonic acid to produce the mesylate salt trihydrate. In this method, half of the racemic mixture of syn-enantiomers formed in the first step has the undesired (1R,2R) stereoconfiguration, which must be separated and discarded in the subsequent resolution step.
A related application (U.S. Ser. No. 09/840,580 filed Apr. 23, 2001), describes process improvements which allow a more efficient D-(xe2x88x92)-tartaric acid resolution of the syn-enantiomers and allows the direct conversion of the D-(xe2x88x92)-tartrate salt to the mesylate salt without intermediate conversion to the free base.
In a related application (Ser. No. 09/840,668 filed on Apr. 23, 2001) both enantiomers of the racemic ketone starting material are converted into a diaroyl D-tartrate salt of the (2S)-enantiomer (formula II, R=benzyl) by a dynamic resolution using a diaroyl D-tartaric acid. After neutralization to the free base, the enantiomerically pure ketone is reduced with hydride to produce the (1S,2S)-enantiomer of formula I having R=benzyl. Debenzylation produces (1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol (formula I, R=H), which is subsequently converted to its mesylate salt. The dynamic resolution of the ketone, in which both enantiomers are converted into one, avoids the wasteful resolution of the alcohol in the earlier process, in which the undesired enantiomer is discarded.
The present invention provides a process for the preparation of a nonracemic chiral alcohol by hydrogenation of a ketone using a catalyst system comprising ruthenium, a nonracemic chiral diphosphine ligand, a bidentate amine ligand selected from an amino-thioether and an achiral diamine, and a base. The inventors have surprisingly found, contrary to the teachings of the background references, that a chiral diamine ligand is not required to obtain highly enantioselective hydrogenation of a ketone to a nonracemic chiral alcohol when using a catalyst system comprising ruthenium, a nonracemic chiral diphosphine ligand, an amine ligand and a base. Accordingly, the present invention provides highly enantioselective hydrogenation of a ketone to a nonracemic chiral alcohol using a bidentate amine ligand selected from a monoamine-thioether and an achiral diamine, when using a catalyst system also comprising ruthenium, a nonracemic chiral diphosphine ligand, and a base.
In one group of embodiments the base is selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes.
In one particular embodiment, the present invention provides a process for the preparation of a nonracemic diastereomer selected from 1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol having the structural formula I and stereoisomers thereof, wherein R is hydrogen or a hydroxyl-protecting group by hydrogenation of a corresponding nonracemic 1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanone compound having formula II or the enantiomer thereof using a catalyst system comprising ruthenium, a nonracemic chiral diphosphine ligand, a bidentate amine ligand selected from amino-thioethers and achiral diamines, and a base.